anti-leukemic activity of FLT3 inhibitor on childhood acute lymphoblastic leukemia with 11q23 translocation

我们检测了PKC412 （FLT3的激酶抑制剂）对具有或不具有D835突变的11q23易位白血病细胞系的抗白血病活性，并探讨了其活性的分子机制。在实时PCR分析中，11q23易位的b -前体白血病细胞系表达了更高的FLT3转录物，与其他b -前体细胞系相比，PKC412对^ 3h -胸腺嘧啶吸收的抑制作用更高。PKC412的这种抗白血病活性在D835突变的11q23易位细胞系中得到更深入的揭示，主要通过caspase依赖性诱导细胞凋亡介导。在携带或不携带D835突变的11q23易位细胞系中也发现了pkc412诱导的细胞周期阻滞在G0/G1期。在PKC412处理后信号分子的变化中，STAT5和Akt的组成磷酸化几乎完全被消除，促凋亡的BH3-only成员Bim显著上调，提示它们在PKC412诱导的细胞凋亡中起着致病作用。这些结果揭示了FLT3抑制剂抗白血病活性的分子机制，并为PKC412可能成为治疗11q23易位白血病，特别是FLT3- tkd突变白血病的潜在有用药物提供了分子基础。

We examined the anti-leukemic activity of PKC412 (a kinase inhibitor of FLT3) against 11q23-translocated leukemia cell lines with or without D835 mutation and pursued the molecular mechanism(s) of its activity. B-precursor leukemic cell lines with 11q23 translocation expressed a higher FLT3 transcript on the real-time PCR analysis and showed a higher inhibition of ^3H-thymidine uptakes by PKC412 when compared with other B-precursor cell lines. This anti-leukemic activity of PKC412 was more profoundly revealed in 11q23-traslocated cell lines with D835 mutation, and was mainly mediated by the caspase-dependent induction of apoptosis. The PKC412-induced cell cycle arrest at the G0/G1 phase was also revealed in 11q23-translocated cell lines with or without D835 mutation. Regarding changes in signaling molecules after PKC412 treatment, constitutive phosphorylation of STAT5 and Akt was almost completely abolished and the proapoptotic BH3-only member Bim was strikingly upregulated, suggesting their causative roles in the PKC412-induced apoptosis. These results shed light on the molecular mechanism of the anti-leukemic activity of the FLT3 inhibitor(s) and provide a molecular basis to the prospect that PKC412 might become a potentially useful agent for the treatment of leukemia with 11q23 translocation, particularly having FLT3-TKD mutations.